EDITORIALS
Optimal heart rate control for patients with chronic atrial fibrillation: Are pharmacologic choices truly changing? Barbara J. Zarowitz, PharmD,
and Mihai
Gheorghiade,
Chronic atria1 fibrillation (CAF) is a common cardiac arrhythmia that occurs frequently in elderly patients with ischemic, hypertensive, or valvular heart disease.ly 2 In the Framingham Study there was a 2 % chance of developing CAF over two decades, and its occurrence was associated with a doubling in mortality.3 Treatment of CAF is primarily directed toward control of the ventricular response rate, as there has been mixed success at restoring sinus rhythm.4 A recent meta-analysis of six independent, double-blind, placebo-controlled studies of quinidine in 800 patients with a history of CAF revealed greater efficacy of quinidine than placebo in preventing recurrence, but this was associated with a threefold greater risk of dying.5 Management of CAF therefore consists primarily of long-standing anticoagulation, with either aspirin or warfarin to prevent systemic embolization, and control of the ventricular response rate.6 The ideal agent for control of heart rate in patients with CAF should be effective both at rest and during exercise; should possess no contraindications; should produce no unwanted effects; should be available for once-daily administration; and should be inexpensive. In patients except those with lone CAF, selection of agents for control of the ventricular response rate is complicated by underlying diseases that may predispose patients to adverse drug consequences.2 Monotherapy with digoxin has been shown to slow the resting ventricular rate in most patients with CAF, but because digoxin’s predominant effect on the resting heart rate is mediated by an enhanced vagal tone, the beneficial effects frequently may not From the Henry Ford Hospital. Received for publication Oct. 10, 1991; accepted Nov. 28, 1991. Reprint requests: Barbara J. Zerowitz, PharmD, Department of Pharmacy Services, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202. 4/1/35979
MD. Detroit,
Mich.
be maintained during exertion when vagal influences are withdrawn7-lo In some patients during even mild effort (3 minutes of exercise), digoxin doses of 0.5 mg/day reduce the heart rate by a mean of only 8% (160 + 24 to 147 -t 29 beats/min).8 Digoxin’s advantages as a once-daily, inexpensive, and relatively safe pharmacologic choice with no contraindications for the control of heart rate in patients with CAF may be outweighed in some patients by the drug’s inability to maintain rate control during exercise and possibly during normal daytime activities, as opposed to rest. Others4 have questioned its role in the ’90s. In the last few years, relatively high doses of fl-adrenergic blocking agents and calcium channel antagonists have been shown to be more effective than placebo and digoxin in controlling exercise-induced increases in the ventricular response rate.7l 8*lo, I1 However, the combination of digoxin with either timolol,7 verapamil,s or diltiazemlO produced greater decreases in heart rate than either digoxin or the added agent alone. This suggests that the combination of /3-adrenergic blockers or calcium channel antagonists with digoxin may be optimal therapy for control of exertional rate increases in CAF. However, the side effects experienced by diltiazem (9 of 12 patients) and timolol (11 of 28 patients) recipients ranged from fatigue and headache to worsening of congestive heart failure, necessitating drug discontinuation (1 of 12 diltiazem patients; 3 of 28 timolol patients).7T lo Limited conclusions can be drawn from these small studies. Although patients were exercised on a bicycle under controlled conditions for a predetermined length of time in both studies, these conditions may not adequately mimic comparable exertion experienced in the daily life-styles of CAF patients. A more meaningful assessment by 24-hour Holter recordings in combination with exercise testing is needed. The role and safety of standard doses of calcium 1401
May 1992
1402
Zarowitz
and Gheorghiade
Table I. Comparative Agent
Digoxin (Lanoxin) Diltiazem (Card&m)
American
characteristics Mean
daily
dose
of pharmacologic Schedule
0.25-0.5 mg
Q day
180-360 mg
TID or QID
Side
atrial
Metoprolol (Lopressor)
loo-450 mg
TID
Propranolol (Inderal) (Inderal-LA)
160-480 mg
TID or &ID
Verapamil (Calan)
240-360 mg
cost*
effects
Nausea, vomiting arrhythmias, CNS effects Angina (1 %), CHF, arrhythmias, edema, headache (8% -12% ), dizziness (6%-7%), nausea (l%-3%) Bradycardia, CHF, hypotension, SOB, dizziness, tiredness, headache, diarrhea, nausea, gastric pain, nightmares Same as metoprolol
Q day TID or &ID
Arrhythmias (4 % ), hradycardia (ll%), constipation (9%), dizziness (4%), headache (2% ), CHF
0.25 mg-$9.40 60 mg-$53.44 120 mg-$100.31 90 120 50 100
mg-$70.00 mg-$91.25 mg-$42.85 mg-$64.38
40 80 60 120 80 120
mg-$41.43 mg-$64.79 mg-$56.23 mg-$81.50 mg-$39.54 mg-$53.48
180 mg-$93.53
Q day
SR, Sustained-Release; LA, long-acting; CNS, central nervous system; CHF, congestive heart failure; *Average wholesale price according to 1992 Drug Topics Red Book, based on 100 tablets each.
channel antagonists and B-blockers (Table I) in patients with congestive heart failure remains controversial. Verapamil and diltiazem have negative inotropic effects that may cause hemodynamic deterioration, particularly in patients with marked left ventricular dysfunction, although diltiazem’s effects appear to be lesspronounced.12-14p-Adrenergic blockers, which also exert negative inotropic effects, cannot only precipitate congestive heart failure but also may be contraindicated in patients with underlying bronchospasm caused by asthma or chronic obstructive pulmonary disease. 15-la In effective doses (equivalent to 150 to 200 mg of propranolol/day) metoprolol has been associated with a loss of cardioselectivity, thereby limiting its utility in patients with pulmonary disease.16-ls Therefore although it has been suggested that ,&adrenergic blockers or calcium channel antagonists may be preferred agents over digoxin, it is not clear that either class of drugs can be safely recommended for CAF patients with underlying eardisc or pulmonary disease, particularly when relatively high doses are needed for rate control. Diltiazem and metoprolol may be the best choices in these two classes of drugs to minimize the negative inotropic and pulmonary effects of calcium channel blockers and @-blockers, respectively, although this has not been shown conclusively. Table I compares side effects, dosing regimens, and average wholesale prices of digoxin, verapamil, diltiazem, and metoprolol. The necessity for multiple
Journal
fibrillationlg
Q day
(Cardizem-SR)
(Calan-SR)
agents used in chronic
Heart
SOB, shortness
of breath.
daily dosing at increased cost to the patient or to third party payers deters from the selection of calcium channel blockers or @-blocking agents over digoxin as primary therapy. Long-acting or sustained-release products may be chosen to decrease the dosing frequency and to improve compliance, but cost remains comparatively high. In addition, although similar central nervous system, gastrointestinal, and cardiovascular side effects have been described for all three classes of drugs, the frequency and severity of consequences requiring drug discontinuation is higher for calcium channel blockers and P-blockers than for digoxin.7> 6 lo Suggestions that calcium channel antagonists or ,8-adrenergic blocking agents may be preferred agents over digoxin for CAF have not been substantiated. Although the efficacy of these agents is comparable, patients with underlying left ventricular dysfunction or bronchospasm may not be able to tolerate regimens that use calcium channel antagonists orp-blockers. Alternatively, proponents of high-dose digoxin as a single agent for CAF must address the concerns of uncontrolled ventricular response rates and symptoms with exercise, as well as the risks of digoxin toxicity. A carefully controlled multicenter trial examining the comparative effectiveness and safety of digoxin versus digoxin plus calcium channel antagonists or P-adrenergic blockers is needed. Meaningful exercise end points such as time to fatigue and peak performance should be examined as well as 24-hour
Volume123 Number 5
Holter monitoring to assess the adequacy of ventricular rate control during daily activities. Perhaps combination therapy will provide optimal resting and exertional control of heart rate while minimizing side effects. This is particularly important because in the presence of therapeutic quantities of digoxin, small doses of P-adrenergic blocking agents or calcium channel antagonists that are usually tolerated by patients with severe heart failure or pulmonary disease may be effective in controlling the ventricular response rate during exercise or in states in which sympathetic tone is increased. Inconclusive evidence exists to advocate using digoxin, calcium channel antagonists, P-adrenergic blockers, or a combination as “best” therapy for controlling CAF. Until such time as prospective controlled trials are performed, it is reasonable to approach the heart rate management of CAF with optimized digoxin therapy alone, as there are no contraindications to the drug, it is inexpensive, and it can be given once daily. Following Holter assessment, if the ventricular response rate remains uncontrolled, the addition of low-dose /3-adrenergic blockers or calcium channel antagonists may be appropriate even in patients with underlying heart failure. REFERENCES
1. Kulbertus HE, Leval-Rutten F, Bartsch P, Petit J. Atrial fibrillation in elderly ambulatory patients. In: Kulbertus H, Olsson SB. SchleDDer M. eds. Atrial fibrillation. Molndal. Sweden: AB Has&, 1984:148-55. 2. Horowitz LN. Atria1 fibrillation. In: Horowitz LN, ed. Current management of arrhythmias. Philadelphia: BC Decker, Inc, 1991:51-8. 3. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atria1 fibrillation: the Framingham Study. N Engl J Med 1982;306:1018-22. 4. Falk RH, Leavitt JI. Digoxin for atria1 fibrillation: a drug whose time has gone? Ann Intern Med 1991;114:573-5. 5. Conlen SE. Antmann EM. Berlin JA. Hewitt P. Chalmers TC. Ef&acy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a meta-analysis of randomized control trials. Circulation 1990;82:1106-16.
Optimal heart rate control in chronic AF
1403
6. Stroke Preventions in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-39. 7. David D, Segni ED, Klein HO, Kaplinsky E. Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta-adrenergic agent. Am J Cardiol 1979;44:1378-82. 8. Lang R, Klein HO, Weiss E, David D, Sareli P, Levy A, Guerrero J, Segni ED, Kaplinsky E. Superiority of oral verapamil therapy to digoxin in treatment of chronic atrial fibrillation. Chest i983;8$491-9. 9. Beasley R, Smith DA, McHafFie DJ. Exercise heart rates at different serum digoxin concentrations in patients with atria1 fibrillation. Br Med J 1985;290:9-11. 10. Roth A, Harrison E, Mitani G, Cohen J, Rahimtoola SH, Elkavam U. Efficacv and safetv of mediumand hiah-dose diltiazem alone and h combination with digoxin for coitrol of heart rate at rest and during exercise in patients with chronic atria1 fibrillation. Circulation 1986;73:316-24. 11. Salerno DM, Dias VC, Kleiger RE, Tschida VH, Sung RJ, Sami M, Giorgi LV. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atria1 flutter. Am J Cardiol 1989;63:1046-51. 12. Bohm M, Schwinger RHG, Erdmann E. Different cardiodepressant potency of various calcium channel antagonists in human myocardium. Am J Cardiol 1990;65:1039-41. 13. Chew CYC, Hecht HS, Collett JT, McAllister RG, Singh BN. Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease. Am J Cardiol 1981;47:917-22. 14. Walsh RW, Porter CB, Starling MR, O’Rourke RA. Beneficial hemodynamic effects of intravenous and oral diltiazem in severe congestive heart failure. J Am Co11 Cardiol 1984;3:104450. 15. Adam WR, Meagher EJ, Barter CE. Labetalol, beta blockers, and acute deterioration of chronic airway obstruction. Clin Exp Hypertens Theory Pratt 1982;A4:1419-28. 16. Formgren H. The effect of metoprolol and practolol on lung function and blood pressure in hypertensive asthmatics. Br J Clin Pharmacol 1976;3:1007-14. 17. Johnson G. Effects of intravenous propranolol and metoprolol and their interaction with isoprenaline on pulmonary function, heart rate and blood pressure in asthmatics. Eur J Clin Pharmacol 1975;8:175-80. 18. Singh BN, Whitlock RML, Comber RH, Williams FH, Harris EA. Effects of cardioselective beta-adrenoreceptor blockade on specific airways resistance in normal subjects and in natienta with bronchial asthma. Clin Pharmacol Ther i976;719:493-501. 19. American Hospital Formulary Service. Bethesda, Md: American Society of Hospital Pharmacists, 1991.
Optimal heart rate control for patients with chronic atrial fibrillation: Are pharmacologic choices truly changing? Barbara J. Zarowitz, PharmD,
and Mihai
Gheorghiade,
Chronic atria1 fibrillation (CAF) is a common cardiac arrhythmia that occurs frequently in elderly patients with ischemic, hypertensive, or valvular heart disease.ly 2 In the Framingham Study there was a 2 % chance of developing CAF over two decades, and its occurrence was associated with a doubling in mortality.3 Treatment of CAF is primarily directed toward control of the ventricular response rate, as there has been mixed success at restoring sinus rhythm.4 A recent meta-analysis of six independent, double-blind, placebo-controlled studies of quinidine in 800 patients with a history of CAF revealed greater efficacy of quinidine than placebo in preventing recurrence, but this was associated with a threefold greater risk of dying.5 Management of CAF therefore consists primarily of long-standing anticoagulation, with either aspirin or warfarin to prevent systemic embolization, and control of the ventricular response rate.6 The ideal agent for control of heart rate in patients with CAF should be effective both at rest and during exercise; should possess no contraindications; should produce no unwanted effects; should be available for once-daily administration; and should be inexpensive. In patients except those with lone CAF, selection of agents for control of the ventricular response rate is complicated by underlying diseases that may predispose patients to adverse drug consequences.2 Monotherapy with digoxin has been shown to slow the resting ventricular rate in most patients with CAF, but because digoxin’s predominant effect on the resting heart rate is mediated by an enhanced vagal tone, the beneficial effects frequently may not From the Henry Ford Hospital. Received for publication Oct. 10, 1991; accepted Nov. 28, 1991. Reprint requests: Barbara J. Zerowitz, PharmD, Department of Pharmacy Services, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202. 4/1/35979
MD. Detroit,
Mich.
be maintained during exertion when vagal influences are withdrawn7-lo In some patients during even mild effort (3 minutes of exercise), digoxin doses of 0.5 mg/day reduce the heart rate by a mean of only 8% (160 + 24 to 147 -t 29 beats/min).8 Digoxin’s advantages as a once-daily, inexpensive, and relatively safe pharmacologic choice with no contraindications for the control of heart rate in patients with CAF may be outweighed in some patients by the drug’s inability to maintain rate control during exercise and possibly during normal daytime activities, as opposed to rest. Others4 have questioned its role in the ’90s. In the last few years, relatively high doses of fl-adrenergic blocking agents and calcium channel antagonists have been shown to be more effective than placebo and digoxin in controlling exercise-induced increases in the ventricular response rate.7l 8*lo, I1 However, the combination of digoxin with either timolol,7 verapamil,s or diltiazemlO produced greater decreases in heart rate than either digoxin or the added agent alone. This suggests that the combination of /3-adrenergic blockers or calcium channel antagonists with digoxin may be optimal therapy for control of exertional rate increases in CAF. However, the side effects experienced by diltiazem (9 of 12 patients) and timolol (11 of 28 patients) recipients ranged from fatigue and headache to worsening of congestive heart failure, necessitating drug discontinuation (1 of 12 diltiazem patients; 3 of 28 timolol patients).7T lo Limited conclusions can be drawn from these small studies. Although patients were exercised on a bicycle under controlled conditions for a predetermined length of time in both studies, these conditions may not adequately mimic comparable exertion experienced in the daily life-styles of CAF patients. A more meaningful assessment by 24-hour Holter recordings in combination with exercise testing is needed. The role and safety of standard doses of calcium 1401
May 1992
1402
Zarowitz
and Gheorghiade
Table I. Comparative Agent
Digoxin (Lanoxin) Diltiazem (Card&m)
American
characteristics Mean
daily
dose
of pharmacologic Schedule
0.25-0.5 mg
Q day
180-360 mg
TID or QID
Side
atrial
Metoprolol (Lopressor)
loo-450 mg
TID
Propranolol (Inderal) (Inderal-LA)
160-480 mg
TID or &ID
Verapamil (Calan)
240-360 mg
cost*
effects
Nausea, vomiting arrhythmias, CNS effects Angina (1 %), CHF, arrhythmias, edema, headache (8% -12% ), dizziness (6%-7%), nausea (l%-3%) Bradycardia, CHF, hypotension, SOB, dizziness, tiredness, headache, diarrhea, nausea, gastric pain, nightmares Same as metoprolol
Q day TID or &ID
Arrhythmias (4 % ), hradycardia (ll%), constipation (9%), dizziness (4%), headache (2% ), CHF
0.25 mg-$9.40 60 mg-$53.44 120 mg-$100.31 90 120 50 100
mg-$70.00 mg-$91.25 mg-$42.85 mg-$64.38
40 80 60 120 80 120
mg-$41.43 mg-$64.79 mg-$56.23 mg-$81.50 mg-$39.54 mg-$53.48
180 mg-$93.53
Q day
SR, Sustained-Release; LA, long-acting; CNS, central nervous system; CHF, congestive heart failure; *Average wholesale price according to 1992 Drug Topics Red Book, based on 100 tablets each.
channel antagonists and B-blockers (Table I) in patients with congestive heart failure remains controversial. Verapamil and diltiazem have negative inotropic effects that may cause hemodynamic deterioration, particularly in patients with marked left ventricular dysfunction, although diltiazem’s effects appear to be lesspronounced.12-14p-Adrenergic blockers, which also exert negative inotropic effects, cannot only precipitate congestive heart failure but also may be contraindicated in patients with underlying bronchospasm caused by asthma or chronic obstructive pulmonary disease. 15-la In effective doses (equivalent to 150 to 200 mg of propranolol/day) metoprolol has been associated with a loss of cardioselectivity, thereby limiting its utility in patients with pulmonary disease.16-ls Therefore although it has been suggested that ,&adrenergic blockers or calcium channel antagonists may be preferred agents over digoxin, it is not clear that either class of drugs can be safely recommended for CAF patients with underlying eardisc or pulmonary disease, particularly when relatively high doses are needed for rate control. Diltiazem and metoprolol may be the best choices in these two classes of drugs to minimize the negative inotropic and pulmonary effects of calcium channel blockers and @-blockers, respectively, although this has not been shown conclusively. Table I compares side effects, dosing regimens, and average wholesale prices of digoxin, verapamil, diltiazem, and metoprolol. The necessity for multiple
Journal
fibrillationlg
Q day
(Cardizem-SR)
(Calan-SR)
agents used in chronic
Heart
SOB, shortness
of breath.
daily dosing at increased cost to the patient or to third party payers deters from the selection of calcium channel blockers or @-blocking agents over digoxin as primary therapy. Long-acting or sustained-release products may be chosen to decrease the dosing frequency and to improve compliance, but cost remains comparatively high. In addition, although similar central nervous system, gastrointestinal, and cardiovascular side effects have been described for all three classes of drugs, the frequency and severity of consequences requiring drug discontinuation is higher for calcium channel blockers and P-blockers than for digoxin.7> 6 lo Suggestions that calcium channel antagonists or ,8-adrenergic blocking agents may be preferred agents over digoxin for CAF have not been substantiated. Although the efficacy of these agents is comparable, patients with underlying left ventricular dysfunction or bronchospasm may not be able to tolerate regimens that use calcium channel antagonists orp-blockers. Alternatively, proponents of high-dose digoxin as a single agent for CAF must address the concerns of uncontrolled ventricular response rates and symptoms with exercise, as well as the risks of digoxin toxicity. A carefully controlled multicenter trial examining the comparative effectiveness and safety of digoxin versus digoxin plus calcium channel antagonists or P-adrenergic blockers is needed. Meaningful exercise end points such as time to fatigue and peak performance should be examined as well as 24-hour
Volume123 Number 5
Holter monitoring to assess the adequacy of ventricular rate control during daily activities. Perhaps combination therapy will provide optimal resting and exertional control of heart rate while minimizing side effects. This is particularly important because in the presence of therapeutic quantities of digoxin, small doses of P-adrenergic blocking agents or calcium channel antagonists that are usually tolerated by patients with severe heart failure or pulmonary disease may be effective in controlling the ventricular response rate during exercise or in states in which sympathetic tone is increased. Inconclusive evidence exists to advocate using digoxin, calcium channel antagonists, P-adrenergic blockers, or a combination as “best” therapy for controlling CAF. Until such time as prospective controlled trials are performed, it is reasonable to approach the heart rate management of CAF with optimized digoxin therapy alone, as there are no contraindications to the drug, it is inexpensive, and it can be given once daily. Following Holter assessment, if the ventricular response rate remains uncontrolled, the addition of low-dose /3-adrenergic blockers or calcium channel antagonists may be appropriate even in patients with underlying heart failure. REFERENCES
1. Kulbertus HE, Leval-Rutten F, Bartsch P, Petit J. Atrial fibrillation in elderly ambulatory patients. In: Kulbertus H, Olsson SB. SchleDDer M. eds. Atrial fibrillation. Molndal. Sweden: AB Has&, 1984:148-55. 2. Horowitz LN. Atria1 fibrillation. In: Horowitz LN, ed. Current management of arrhythmias. Philadelphia: BC Decker, Inc, 1991:51-8. 3. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atria1 fibrillation: the Framingham Study. N Engl J Med 1982;306:1018-22. 4. Falk RH, Leavitt JI. Digoxin for atria1 fibrillation: a drug whose time has gone? Ann Intern Med 1991;114:573-5. 5. Conlen SE. Antmann EM. Berlin JA. Hewitt P. Chalmers TC. Ef&acy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a meta-analysis of randomized control trials. Circulation 1990;82:1106-16.
Optimal heart rate control in chronic AF
1403
6. Stroke Preventions in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-39. 7. David D, Segni ED, Klein HO, Kaplinsky E. Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta-adrenergic agent. Am J Cardiol 1979;44:1378-82. 8. Lang R, Klein HO, Weiss E, David D, Sareli P, Levy A, Guerrero J, Segni ED, Kaplinsky E. Superiority of oral verapamil therapy to digoxin in treatment of chronic atrial fibrillation. Chest i983;8$491-9. 9. Beasley R, Smith DA, McHafFie DJ. Exercise heart rates at different serum digoxin concentrations in patients with atria1 fibrillation. Br Med J 1985;290:9-11. 10. Roth A, Harrison E, Mitani G, Cohen J, Rahimtoola SH, Elkavam U. Efficacv and safetv of mediumand hiah-dose diltiazem alone and h combination with digoxin for coitrol of heart rate at rest and during exercise in patients with chronic atria1 fibrillation. Circulation 1986;73:316-24. 11. Salerno DM, Dias VC, Kleiger RE, Tschida VH, Sung RJ, Sami M, Giorgi LV. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atria1 flutter. Am J Cardiol 1989;63:1046-51. 12. Bohm M, Schwinger RHG, Erdmann E. Different cardiodepressant potency of various calcium channel antagonists in human myocardium. Am J Cardiol 1990;65:1039-41. 13. Chew CYC, Hecht HS, Collett JT, McAllister RG, Singh BN. Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease. Am J Cardiol 1981;47:917-22. 14. Walsh RW, Porter CB, Starling MR, O’Rourke RA. Beneficial hemodynamic effects of intravenous and oral diltiazem in severe congestive heart failure. J Am Co11 Cardiol 1984;3:104450. 15. Adam WR, Meagher EJ, Barter CE. Labetalol, beta blockers, and acute deterioration of chronic airway obstruction. Clin Exp Hypertens Theory Pratt 1982;A4:1419-28. 16. Formgren H. The effect of metoprolol and practolol on lung function and blood pressure in hypertensive asthmatics. Br J Clin Pharmacol 1976;3:1007-14. 17. Johnson G. Effects of intravenous propranolol and metoprolol and their interaction with isoprenaline on pulmonary function, heart rate and blood pressure in asthmatics. Eur J Clin Pharmacol 1975;8:175-80. 18. Singh BN, Whitlock RML, Comber RH, Williams FH, Harris EA. Effects of cardioselective beta-adrenoreceptor blockade on specific airways resistance in normal subjects and in natienta with bronchial asthma. Clin Pharmacol Ther i976;719:493-501. 19. American Hospital Formulary Service. Bethesda, Md: American Society of Hospital Pharmacists, 1991.
